Original article: CGS 16949A, a new aromatase inhibitor in the treatment of breast cancer — A Phase I study

Summary Forty-six postmenopausal women with either locally advanced or metastatic breast cancer were treated with the aromatase inhibitor CGS 16949A in three different daily doses (0.3 mg, 0.6 mg and 0.9 mg total daily dose). 41 patients (89%) were pretreated by endocrine treatment for metastatic disease; 30 of these 41 were also pretreated with chemotherapy. Of the remaining 5 patients (11%) 3 were previously treated with chemotherapy alone and 2 were not pretreated. Evaluable sites of disease were: skin and soft tissue (including local recurrence) in 34, bone in 31, lung in 14 and viscera in 13 instances, respectively. 1 PR (3%) and 9 stable diseases (24%) were observed in the 37 patients assessable for response. All but two of these results were observed in the 0.9 mg group. Time to progression was 14 months for the patient showing a PR, and the median time to progression for those with stable disease was 6 months (range 6 to 23 months). Plasma estradiol and estrone levels were measured in patients receiving the daily dose of 0.6 mg (n = 4) and 0.9 mg (n = 15). The estrone levels decreased from a mean of 23.1 pg/mL (SD 17.1) to 10.5 pg/mL (SD 6.6) in the 0.6 mg-group and from 21.2 pg/mL (SD 18.9) to 9.1 pg/mL (SD 5.5) in the 0.9 mg-group within 4 days of drug administration (p < 0.0001 from baseline in both groups, with no significant difference between doses). Plasma estradiol levels decreased from 12 pg/mL (SD 12.6) to 6.0 pg/mL (SD 3.6) in the 0.6 mg-group and from 9.5 pg/mL (SD 6.5) to 6.1 pg/mL (SD 2.6) in the 0.9 mg-group (p < 0.01). The suppression of estradiol and estrone was maintained during the subsequent measurements on days 8 and 29 in the 0.9 mg group (n = 14). There was no significant change over time in cortisol levels, nor was there any significant difference between the three doses at any given time. Toxicity was mostly mild and consisted mainly of loss of appetite (7/46 = 15%), fatigue (5/46 = 11%) and nausea (4/46 = 9%) at all three dose levels. We conclude that the aromatase inhibitor CGS 16949A is well tolerated within the ranges tested and does not affect the cortisol level. Although, as observed by others, suppression of plasma estrone might be enhanced by higher doses of CGS 16949A, some antitumor effect can already be seen with 0.9 mg daily.